References:
The following references are referred to by numbers in brackets ([ ]) at the relevant portion of the specification.
1. Zoladex (goserelin acetate implant), Physician's Desk Reference, 50th Edition, pages 2858-2861 (1996). PA0 2. U.S. Pat. No. 3,914,412, issued Oct. 21, 1975. PA0 3. U.S. Pat. No. 4,547,370, issued Oct. 15, 1985. PA0 4. U.S. Pat. No. 4,661,472, issued Apr. 28, 1987. PA0 5. U.S. Pat. No. 4,689,396, issued Aug. 25, 1987. PA0 6. U.S. Pat. No. 4,851,385, issued Jul. 25, 1989. PA0 7. U.S. Pat. No. 5,198,533, issued Mar. 30, 1993. PA0 8. U.S. Pat. No. 5,480,868, issued Jan. 2, 1996. PA0 9. WO92/2071 1, published Nov. 26, 1992. PA0 10. WO95/00168, published Jan. 5, 1995. PA0 11. WO95/04540, published Feb. 16, 1995. PA0 12. "Stability of Gonadorelin and Triptorelin in Aqueous Solution", V. J. Helm, B. W. Muller, Pharmaceutical Research, 7/12, pages 1253-1256 (1990). PA0 13. "New Degradation Product of Des-Gly.sup.10 -NH.sub.2 -LH-RH-Ethylamide (Fertirelin) in Aqueous Solution", J. Okada, T. Seo, F. Kasahara, K. Takeda, S. Kondo, J. of Pharmaceutical Sciences, 80/2, pages 167-170 (1991). PA0 14. "Characterization of the Solution Degradation Product of Histrelin, a Gonadotropin Releasing Hormone (LHRH) Agonist", A. R. Oyler, R. E. Naldi, J. R. Lloyd, D. A. Graden, C. J. Shaw, M. L. Cotter, J. of Pharmaceutical Sciences, 80/3, pages 271-275 (1991). PA0 15. "Parenteral Peptide Formulations: Chemical and Physical Properties of Native Luteinizing Hormone-Releasing Hormone (LHRH) and Hydrophobic Analogues in Aqueous Solution", M. F. Powell, L. M. Sanders, A. Rogerson, V. Si, Pharmaceutical Research, 8/10, pages 1258-1263 (1991). PA0 16. "Degradation of the LHRH Analog Nafarelin Acetate in Aqueous Solution", D. M. Johnson, R. A. Pritchard, W. F. Taylor, D. Conley, G. Zuniga, K. G. McGreevy, Intl. J. of Pharmaceutics, 31, pages 125-129 (1986). PA0 17. "Percutaneous Absorption Enhancement of Leuprolide", M. Y. Fu Lu, D. Lee, G. S. Rao, Pharmaceutical Research, 9/12, pages 1575-1576 (1992). PA0 18. Lutrepulse (gonadorelin acetate for IV injection), Physician's Desk Reference, 50th Edition, pages 980-982 (1996). PA0 19. Factrel (gonadorelin HCl for subcutaneous or IV injection), Physician's Desk Reference, 50th Edition, pages 2877-2878 (1996). PA0 20. Lupron (leuprolide acetate for subcutaneous injection), Physician's Desk Reference, 50th Edition, pages 2555-2556 (1996). PA0 21. Lupron depot (leuprolide acetate for depot suspension), Physician's Desk Reference, 50th Edition, pages 2556-2562 (1996). PA0 22. "Pharmaceutical Manipulation of Leuprorelin Acetate to Improve Clinical Performance", H. Toguchi, J. of Intl. Medical Research, 18, pages 35-41 (1990). PA0 23. "Long-Term Stability of Aqueous Solutions of Luteinizing Hormone-Releasing Hormone Assessed by an In-Vitro Bioassay and Liquid Chromatography", Y. F. Shi, R. J. Sherins, D. Brightwell, J. F. Gallelli, D. C. Chatterji, J. of Pharmaceutical Sciences, 73/6, pages 819-821 (1984). PA0 24. "Peptide Liquid Crystals: Inverse Correlation of Kinetic Formation and Thermodynamic Stability in Aqueous Solution", M. F. Powell, J. Fleitman, L. M. Sanders, V. C. Si, Pharmaceutical Research, 11/9, pages 1352-1354 (1994). PA0 25. "Solution Behavior of Leuprolide Acetate, an LHRH Agonist, as Determined by Circular Dichroism Spectroscopy", M. E. Powers, A. Adejei, M. Y. Fu Lu, M. C. Manning, Intl. J. of Pharmaceutics, 108, pages 49-55 (1994). PA0 26. "Preparation of Three-Month Depot Injectable Microspheres of Leuprorelin Acetate Using Biodegradable Polymers", Pharmaceutical Research, 11/8, pages 1143-1147 (1994).
The disclosure of each of the above publications, patents or patent applications is hereby incorporated by reference in its entirety to the same extent as if the language of each individual publication, patent and patent application were specifically and individually incorporated by reference.
Luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin releasing hormone (GnRH), is a decapeptide with the structure:
pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2.
It is secreted by the hypothalamus and binds to receptors on the pituitary gland, releasing luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH stimulate the gonads to synthesize steroid hormones. Numerous analogs of LHRH are known, including peptides related to LHRH which act as agonists and those which act as antagonists. [1-15] LHRH analogs are known to be useful for treating hormone-dependent diseases such as prostate cancer, benign prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, or mammary cancer and as contraceptives. [8] Sustained release administration is preferred for both agonist LHRH-related compounds, which reduce the number of available receptors after repeated administration so that the production of steroid hormones is suppressed, and antagonist LHRH-related compounds, which must be continually administered for persistent inhibition of endogenous LHRH. [8]
The sustained parenteral delivery of drugs, especially peptide drugs, provides many advantages. The use of implantable devices for sustained delivery of a wide variety of drugs or other beneficial agents is well known in the art. Typical devices are described, for example, in U.S. Pat. Nos. 5,034,229; 5,057,318; and 5,110,596. The disclosure of each of these patents is incorporated herein by reference.
In general, oral bioavailability of peptides, including LHRH-related compounds, is low. [16-17]
Currently marketed formulations of LHRH, its analogs and related compounds which are used for parenteral injection are aqueous solutions which contain relatively low concentrations of LHRH-related compounds (0.05 to 5 mg/ml) and may also contain excipients such as mannitol or lactose. [18-20] Such formulations of LHRH-related compounds must either be stored refrigerated or may be stored at room temperature for short periods of time.
Available depot formulations of LHRH-related compounds administered for sustained release over a period of 1-3 months include a formulation comprised of 15% LHRH-related compound dispersed in a matrix of D,L-lactic and glycolic acids copolymer presented as a cylinder to be injected subcutaneously [1] and a formulation comprised of microparticles comprising a core of LHRH-related compound and gelatin surrounded by a shell of D,L-lactic and glycolic acids copolymer. These microparticles are suspended in a diluent for injection either subcutaneously or intramuscularly. [21, 26] These products must be stored at room temperature or lower. Aqueous formulations of LHRH-related compounds are known to exhibit both chemical and physical instability, as well as degradation after irradiation. [12-16, 22-25]
Formulations which have been shown to be stable (t.sub.90 about five years) have been very low concentration (25 .mu.g/ml) aqueous, buffered (10 mM, ionic strength of 0.15) solutions stored at temperatures no higher than room temperature (25.degree. C.). [15]
There is a need for stable formulations of peptides.